Human growth hormone is a protein consisting of a single chain of 191 amino acids. The molecule is cross-linked by two disulphide bridges and the monomeric form has a molecular weight of 22 kDa. However, pituitary human growth hormone is not homogeneous. For example, a smaller 20 kDa hGH variant produced from the same gene is also known. The "basic hGH" variant (hGH-V) expressed by the placenta during pregnancy is another analogue which is a product of a separate gene. Like the 22 kDa hGH it consists of 191 amino acids but in various positions throughout the molecule 13 of them are different.
Recombinant hGH (22 kDa) has been available commercially for several years. It is preferred over the pituitary derived products because the product prepared from human tissue might be contaminated and transmit infections. Of particular concern is the slow virus disease, Creutzfeld-Jacob's disease. Two types of therapeutically useful recombinant hGH preparations are present on the market: the authentic one, e.g. Genotropin.RTM., Kabi Pharmacia AB, and an analogue with an additional methionine residue at the N-terminal end, e.g. Somatonorm.RTM..
By growth hormone (hGH) is here meant any of the above mentioned variants or any functional analogue with human growth hormone activity.
Diabetes mellitus is a chronic syndrome of impaired carbohydrate, protein and fat metabolism secondary to insufficient secretion of insulin or to target tissue insulin resistance. Diabetes mellitus is normally called diabetes. It occurs in two major forms: insulin-dependent diabetes mellitus (type I) and non-insulin-dependent diabetes mellitus (type II).
Hypoglycaemia is an abnormally diminished concentration of glucose in the blood, which may lead to tremor, sweating, piloreaction, hypothermia and ultimately convulsions and coma. This is a dangerous condition for a diabetic patient, especially if it occurs during the night and the patient does not wake up.
Normally, hypoglycaemia leads to an increase in counterregulatory hormones such as catecholamines, cortisol and glucagon.
Hypoglycaemia can occur at any time in an insulin-treated diabetic subject, and is then, when the patient notices the signals, normally treated with carbohydrate intake or administration of glucose to the patient.
Hypoglycemic unawareness is a serious and still unsolved clinical problem in some insulin-dependent diabetic patients. These patients lack the normal warning symptoms of a hypoglycemic episode. Moreover, hypoglycemic unawareness is often associated with inadequate glucose counterregulation during hypoglycaemia. Reference is made to Ryder R. E. J., et al., Brit J Med, 301 (1990) 783-787 and White N. H., et al., N Engl J Med, 308 (1983) 485-491.
We have now surprisingly found that hypoglycemic awareness was restored in a group of diabetic patients during hGH treatment and that the restored awareness lasted for a year or more after completion of the trial.
The necessary dose of growth hormone to provide this effect is estimated to be 1-10 IU given daily and then repeated for at least one week, but can of course go on continuously if needed.
In the study, as reported below, 4 IU of hGH was given every day during one week.
The invention relates to the use of human growth hormone, or any functional analogue therof, for the manufacture of a medicament for the treatment or prophylaxis of hypoglycemic unawareness in diabetes mellitus.
Preferably the human growth hormone, or any functional analogue thereof, is administered repeatedly, which could be daily. The daily dose is between 1-10 IU and could be given at a dose of 4 IU daily during one week.
The invention also relates to a method for treatment and prophylaxis of hypoglycemic unawareness by administration of human growth hormone, or any functional analogue thereof. Preferably the human growth hormone, or functional analogue thereof, is administered daily and given at a dose of 4 IU daily during one week.